The invention relates to a drug preparation which comprises α-lipoic acid, ambroxol and/or an ACE inhibitor (inhibitor of the angiotensin-converting enzyme). Furthermore, the invention relates to the use of a drug preparation for therapeutically treating degenerative diseases of the Central Nervous System (CNS) as, for example, ischemic or hemorrhagic stroke, focal or global ischemia, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Hunntington's disease, Multiple Sclerosis, neurodegeneration of the aged and age-related dementia, trauma and Autosomal Dominant Neurohypophyseal Diabetes Insipidus (ADNDI). Included in the invention is also a use of the preparation according to the invention for the prevention and therapy of cerebral ischemia following cardial and cardiovascular insults. The above-mentioned clinical indications lead to a loss of the function of certain areas of the CNS and result, in almost all cases, into an irreversible mental and physical handicap. A regulative intervention into the cellular thiol status in cases of neurodegenerative diseases intends, on the one hand, to minimize the generation of damage and, on the other hand, to prevent damage in cases of less severely damaged cells in the penumbra.
The cellular thiol/disulfide status is one of the most important basic preconditions of biological metabolic performance. Particularly, the functionality of proteins is influenced to a large extent by the oxidation and reduction of thiol/disulfide groups.
The maintenance and proper function of the metabolism of cleaving disulfide groups and generating thiol groups as controlled by several classes of different enzymes is indispensable for the cell viability in view of its manifold biological functions, inter alia in processes of cellular growth and differentiation including the programmed cell death as well as mechanisms of cell protection and cell decontamination. Disturbances in this metabolic system and changes of the thiol concentration result into severe functional disturbances of the cell which can be restricted locally only in individual cases; usually, such disturbances adversely affect large parts of the tissues concerned and even extend to adjacent tissues or to the whole organism.
The role of a disturbed thiol/disulfide status in the cell, during the generation of neurodegenerative diseases and during their progress as well, was not sufficiently explored, up to now. Hence, there is an urgent need to elucidate the connections between thiol status and the pathophysiology of neurodegenerative diseases, particularly with the aim of finding potent effective agents for the treatment of diseases and damage of the central nervous system for which an equivalent medicament intervention is not yet available up to now.
In the course of a degeneration of neurons after ischemic events, the inhibition of endogenic protection mechanisms plays a vital role, in addition to a damage of the endothelium (change of the barrier function of the blood brain barrier), since many enzymes and regeneration systems are inhibited subsequent to the ischemia [1, 2]. This can be realized particularly during the reperfusion phase.
Not only in cases where a person is affected by a stroke, but also in cases where other neurodegenerative diseases occur, i.e. diseases having an acute or a chronic course, as, for example, Parkinson's disease, Alzheimer's disease [3], aging processes [4, 5], hemorrhagic stroke [6], excitotoxicity [7], ALS and trauma [8], a neuronal damage as a consequence of a lack of protection or regeneration systems or of their inhibition is discussed. It could not yet be elucidated what is the actual contribution thereof. If, however, partial components of those endogeneous protection systems are defect or are present only to a minor extent, as shown here for the example of pyramidal cells, this may have dramatic consequences.
A lack of cellular protection mechanisms results, inter alia, into lipid peroxidation, as a consequence of which the integrity of cellular membranes is lost. By such a mechanism, membrane-bound proteins are affected. In cases of ischemia, for example, glutamate-transporting proteins are affected functionally [8], the function of which is to transport released glutamate back into the cell and to thereby prevent a toxic extracellular concentration of this neurotransmitter molecule from occurring.
α-lipoic acid is used with moderate success up to now as an adjuvant for the treatment of mis-sensations in the frame of peripheric diabetic polyneuropathia (Diabetologica 1995; 38: 1425-1433; Diabetes Res. Clin. Pract. 1995; 29: 19-26; Diab. Care 1999; 22: 1296-1301; Drug Metab. Rev. 1997; 29: 1025-1054; DE 43 43 592 C2). Moreover, in the patent documents DE 44 47 599 C2 and EP 0 530 446 B1, the use of α-lipoic acid for the treatment of further neuronal disturbances as, for example, tinnitus and sudden deafness is protected.
The cytoprotective mechanism in the course of symptoms accompanying diabetes is based not only on influencing the sugar-dependent modification of proteins (glycosylation of proteins) and on decreasing the genesis of toxic ketone bodies, but also on the function of α-lipoic acid and its metabolites as antioxidants [9].
In the patent documents EP 0 812 590 A2 and EP 0 427 247 B1, the use of α-lipoic acid as a peripheric cytoprotective agent, an anti-analgesic agent and as a medicament against inflammation diseases is disclosed.
Ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino-) cyclohexane hydrochloride) is used in several different administration forms as a mucolytical medicament for lung and bronchial diseases (WO 96/33704; GB 2,239,242; WO 01/05378). Moreover, its use against hyperuricemia is known from the document DE 35 30 761. The effect of ambroxol as a mucolytical agent is based on a stimulation of the surfactant production of bronchial cells and, particularly, on its capability of eliminating free radicals as well [10]. The antioxidative activity of said substance based thereon was primarily detected at pulmonal cells [11], but also in the frame of inflammatory mechanisms [12]. Furthermore, it is known that regulatory enzymes of the glutathione metabolism are directly influenced by an addition of ambroxol in large doses [13].
Inhibitors of the angiotensin-converting enzyme (ACE) are very successfully used for the treatment of a broad spectrum of cardiovascular diseases. This class of substances provides their blood pressure-decreasing effect via an inhibition of the transformation of angiotensin-I into angiotensin-II and via an influence on the kinine metabolism, respectively. For influencing intracellular redox processes, one has to distinguish the effects of ACE inhibitors bearing thiol groups as, for example, Captopril (1-[(2S)-3-mercapto-2-meth-ylpropionyl-]L-proline) from the effects of thiol-free ACE inhibitors as, for example, Enalapril (1-{N-[(S)1-ethoxycarbonyl-3-phenylpropyl-]L-alanyl-}L-proline). While the former react directly as radical scavengers and, hence, have an antioxidative effect, the latter SH-free ACE inhibitors are not able to do so primarily. However, a common feature of both groups is their influence on the glutathione redox cycle via a regulation of the glutathione reductase, of the glutathione peroxidase and of the superoxide dismutase (Am. J. Physiol. Regulatory Integrative Comp. Physiol. 2000; 278: 572-577).
Already in the document DE 44 20 102 A1, the use of different medicaments in combination with α-lipoic acid was protected for the improvement of existing drug therapies against cardiovascular and diabetes-caused diseases. The claims of this patent are restricted to those areas of use, with the exception of the combination of α-lipoic acid and calcium antagonists which are not a part of the presently described novel substance combination. In the document DE 44 20 102 A1, the use of a combination of α-lipoic acid and calcium antagonists is claimed for neurodegenerative diseases, exclusively. Subject-matter of the main claim of the document DE 44 20 102 A1 is the differentiation of the different stereoisomers of α-lipoic acid as specifically useable effective agents and specified drug formulations.